The stable crystalline Dihydrate D is particularly important for the commercial development of new formulations of the pharmaceutically active olanzapine. Olanzapine is useful for treating psychotic patients. Often an aqueous formulation or a formulation that is prepared using aqueous mixing is desired. Applicants have discovered that Form II olanzapine is the most stable anhydrous form of olanzapine, providing a stable anhydrous formulation with pharmaceutically desired characteristics. However, a stable dihydrate was desired to provide pharmaceutically elegant aqueous formulations.
A novel dihydrate crystal form of olanzapine has now been synthesized and characterized which possesses distinct advantages over the previously known forms, that is the material produced using the methods described in U.S. Pat. No. 5,299,382 (hereinafter referred to as "the '382 patent"), when aqueous formulations or a stable aqueous intermediate is desired. This novel dihydrate crystal form is clearly distinguishable therefrom by x-ray powder diffractometry. U.S. Pat. No. 5,229,382 is hereby incorporated by reference in its entirety.
Applicants have discovered that Dihydrate D olanzapine is essential to assure a pharmaceutically elegant, aqueous formulation. Applicants have found that olanzapine forms a Dihydrate B; however, this form appears to be quite unstable compared to Dihydrate D. Dihydrate D requires controlled conditions to prepare the substantially pure Dihydrate D material; however, once prepared, the Dihydrate D is surprisingly robust and stable. Therefore, Dihydrate D olanzapine is most desired and appears to be essential for use in preparing consistently stable commercial pharmaceutically elegant aqueous olanzapine formulations as well as for pharmaceutically elegant formulations prepared using extensive aqueous mixing.